Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Neuroblastoma is a cancer of early childhood that arises from the developing autonomic nervous system. It is the most common malignancy diagnosed in the first year of life and shows a wide range of clinical phenotypes with some patients having tumors that regress spontaneously, whereas the majority of patients have aggressive metastatic disease (Maris et al. (2007) Lancet 369:2106-20). These latter neuroblastoma cases have survival probabilities of less then 40% despite intensive chemoradiotherapy, and the disease continues to account for 15% of childhood cancer mortality (Maris et al. (2007) Lancet, 369:2106-20; Matthay et al. (1999) N. Eng. J. Med., 341:1165-73). Tumors from patients with an aggressive phenotype often show amplification of the MYCN oncogene (Schwab et al. (1984) Nature, 308:288-91), and/or deletions of chromosome arms 1p and 11q (Attiyeh et al. (2005) N. Engl. J. Med., 353:2243-53). However, because MYCN is so aberrantly dysregulated, and no putative tumor suppressor gene at 1p and 11q has been shown to harbor inactivating mutations in more than a small percentage of cases, no tractable molecular target approaches currently exist for this disease.
Like most human cancers, a small subset of neuroblastoma cases are inherited in an autosomal dominant manner (Knudson et al. (1972) Amer. J. Hum. Genet., 24:514-522; Kushner et al. (1986) Cancer, 57:1887-1893; Maris et al. (1997) Eur. J. Cancer, 33:1923-1928). A family history of the disease is found in about 1-2% of newly diagnosed cases, with a standardized incidence ratio of 9.7 for siblings of index cases (Friedman et al. (2005) Cancer Epidemiol. Biomarkers Prev., 14:1922-7). Neuroblastoma pedigrees show striking heterogeneity in the type of tumors that arise, with both benign and malignant forms occurring in the same family (Maris et al. in Neuroblastoma (eds. Cheung et al.) 21-26 (Springer, Berlin, Heidelberg, N.Y., 2005). Familial neuroblastoma patients differ from those with sporadic disease in that they are diagnosed at an earlier age and/or with multiple primary tumors, clinical characteristics that are hallmarks of cancer predisposition syndromes. Because of the lethality of the condition prior to reproductive age, previous genetic linkage scans have been underpowered and results difficult to replicate (Longo et al. (2007) Hum. Hered., 63:205-11; Maris et al. (2002) Cancer Res., 62:6651-6658; Perri et al. (2002) Oncogene 21:8356-60). Remarkably, neuroblastoma can occur with a spectrum of disorders related to abnormal development of neural crest derived tissues including central congenital hypoventilation syndrome and Hirschsprung disease. Missense or nonsense mutations in PHOX2B (paired-like homeobox 2B), a homeobox gene that is a master regulator of normal autonomic nervous system development, were recently shown to predispose to this rare field defect of the sympathicoadrenal lineage tissues (Amiel et al. (2003) Nat. Genet., 33:459-61; Mosse et al. (2004) Am. J. Hum. Genet., 75:727-30; Trochet et al. Am. J. Hum. Genet., 74:761-4). However, PHOX2B mutations explain only a small subset of hereditary neuroblastoma, are almost exclusive to cases with associated disorders of neural crest-derived tissues, and are not somatically acquired in tumors (Raabe et al. (2008) Oncogene, 27:469-76; van Limpt et al. (2004) Oncogene, 23:9280-8), leaving the genetic etiology for the majority of familial neuroblastoma cases unknown.